Taro Kariya

Regulation of Mitochondrial Dynamics by Dynamin-Related Protein-1 in Acute Cardiorenal Syndrome

Experimental evidence has clarified distant organ dysfunctions induced by AKI. Crosstalk between the kidney and heart, which has been recognized recently as cardiorenal syndrome, appears to have an important role in clinical settings, but the mechanisms by which AKI causes cardiac injury remain poorly understood. Both the kidney and heart are highly energy-demanding organs that are rich in mitochondria. Therefore, we investigated the role of mitochondrial dynamics in kidney-heart organ crosstalk. Renal ischemia reperfusion (IR) injury was induced by bilateral renal artery clamping for 30 min in 8-week-old male C57BL/6 mice. Electron microscopy showed a significant increase of mitochondrial fragmentation in the heart at 24 h. Cardiomyocyte apoptosis and cardiac dysfunction, evaluated by echocardiography, were observed at 72 h. Among the mitochondrial dynamics regulating molecules, dynamin-related protein 1 (Drp1), which regulates fission, and mitofusin 1, mitofusin 2, and optic atrophy 1, which regulate fusion, only Drp1 was increased in the mitochondrial fraction of the heart. A Drp1 inhibitor, mdivi-1, administered before IR decreased mitochondrial fragmentation and cardiomyocyte apoptosis significantly and improved cardiac dysfunction induced by renal IR. This study showed that renal IR injury induced fragmentation of mitochondria in a fission-dominant manner with Drp1 activation and subsequent cardiomyocyte apoptosis in the heart. Furthermore, cardiac dysfunction induced by renal IR was improved by Drp1 inhibition. These data suggest that mitochondrial fragmentation by fission machinery may be a new therapeutic target in cardiac dysfunction induced by AKI.

Modulation of cardiac fibrosis by Kruppel-like factor 6 through transcriptional control of thrombospondin 4 in cardiomyocytes

AIMS Krüppel-like factors (KLFs) are a family of transcription factors which play important roles in the heart under pathological and developmental conditions. We previously identified and cloned Klf6 whose homozygous mutation in mice results in embryonic lethality suggesting a role in cardiovascular development. Effects of KLF6 on pathological regulation of the heart were investigated in the present study. METHODS AND RESULTS Mice heterozygous for Klf6 resulted in significantly diminished levels of cardiac fibrosis in response to angiotensin II infusion. Intriguingly, a similar phenotype was seen in cardiomyocyte-specific Klf6 knockout mice, but not in cardiac fibroblast-specific knockout mice. Microarray analysis revealed increased levels of the extracellular matrix factor, thrombospondin 4 (TSP4), in the Klf6-ablated heart. Mechanistically, KLF6 directly suppressed Tsp4 expression levels, and cardiac TSP4 regulated the activation of cardiac fibroblasts to regulate cardiac fibrosis. CONCLUSION Our present studies on the cardiac function of KLF6 show a new mechanism whereby cardiomyocytes regulate cardiac fibrosis through transcriptional control of the extracellular matrix factor, TSP4, which, in turn, modulates activation of cardiac fibroblasts.

Multi-scale, tailor-made heart simulation can predict the effect of cardiac resynchronization therapy

BACKGROUND The currently proposed criteria for identifying patients who would benefit from cardiac resynchronization therapy (CRT) still need to be optimized. A multi-scale heart simulation capable of reproducing the electrophysiology and mechanics of a beating heart may help resolve this problem. The objective of this retrospective study was to test the capability of patient-specific simulation models to reproduce the response to CRT by applying the latest multi-scale heart simulation technology. METHODS AND RESULTS We created patient-specific heart models with realistic three-dimensional morphology based on the clinical data recorded before treatment in nine patients with heart failure and conduction block treated by biventricular pacing. Each model was tailored to reproduce the surface electrocardiogram and hemodynamics of each patient in formats similar to those used in clinical practice, including electrocardiography (ECG), echocardiography, and hemodynamic measurements. We then performed CRT simulation on each heart model according to the actual pacing protocol and compared the results with the clinical data. CRT simulation improved the ECG index and diminished wall motion dyssynchrony in each patient. These results, however, did not correlate with the actual response. The best correlation was obtained between the maximum value of the time derivative of ventricular pressure (dP/dtmax) and the clinically observed improvement in the ejection fraction (EF) (r=0.94, p<0.01). CONCLUSIONS By integrating the complex pathophysiology of the heart, patient-specific, multi-scale heart simulation could successfully reproduce the response to CRT. With further verification, this technique could be a useful tool in clinical decision making.

Recovery from Extreme Hemodilution (Hemoglobin Level of 0.6 g/dL) in Cadaveric Liver Transplantation.

Decompensated hepatic failure occurred in a patient with a rare blood type. The patient had extreme hemodilution due to massive bleeding during liver transplantation. A shortage of matched and universal donor blood prompted us to transfuse albumin and fresh frozen plasma for intravascular volume resuscitation. The lowest hemoglobin was 0.6 g/dL, accompanied by ST depression and a serum lactate of 100 mg/dL. The accuracy of the measured value of 0.6 g/dL was confirmed. However, the patient recovered from this critical situation after transfusion, and he was eventually discharged from the hospital without significant sequelae. Maintaining normovolemia, administering pure oxygen, ensuring appropriate anesthetic depth, and maintaining minimal inotropic support were essential for this patient’s survival during massive bleeding.

Ventricular fiber optimization utilizing the branching structure

In this paper, we propose an algorithm that optimizes the ventricular fiber structure of the human heart. A number of histological studies and diffusion tensor magnetic resonance imaging analyses have revealed that the myocardial fiber forms a right-handed helix at the endocardium. However, the fiber formation changes its orientation as a function of transmural depth, becoming a left-handed helix at the epicardium. To determine how nature can construct such a structure, which obtains surprising pumping performance, we introduce macroscopic modeling of the branching structure of cardiac myocytes in our finite element ventricular model and utilize this in an optimization process. We put a set of multidirectional fibers around a central fiber orientation at each point of the ventricle walls and simulate heartbeats by generating contraction forces along each of these directions. We examine two optimization processes using the workloads or impulses measured in these directions to update the central fiber orientation. Both processes improve the pumping performance towards an optimal value within several tens of heartbeats, starting from an almost-flat fiber orientation. However, compared with the workload optimization, the impulse optimization produces better agreement with experimental studies on transmural changes of fiber helix angle, streamline patterns of characteristic helical structures, and temporal changes in strain. Furthermore, the impulse optimization is robust under geometrical changes of the heart and tends to homogenize various mechanical factors such as the stretch and stretch rate along the fiber orientation, the contraction force, and energy consumption. Copyright

Markedly Dilated Right Heart 17 Years After Initial Treatment Repaired by Total Right Ventricular Exclusion and Total Cavopulmonary Connection

The total right ventricular (RV) exclusion procedure for isolated congestive RV failure, in which most of the dilated right atrium (RA) and RV wall is resected, was first reported by Sano et al in 2002.1 This procedure improves the cardiac index2 and suppresses supraventricular/ventricular tachyarrhythmia. Using this procedure with an extracardiac conduit, we successfully treated severe heart failure characterized by a markedly dilated right heart lacking tricuspid leaflets and by recurrent tachyarrhythmia, 17 years after the patient had undergone initial definitive intracardiac repair including RV outflow tract plasty. A 22-year-old woman presented with general fatigue, dyspnea, palpitations, and loss of appetite of 6 months’ duration caused by low cardiac output. She was admitted to the University of Tokyo Hospital to undergo surgery to improve her low cardiac output. She was cyanotic at birth after an uneventful pregnancy and caesarian delivery. Cardiac catheterization performed when she was 47 days old revealed pulmonary atresia with atrial septal defect and patent ductus arteriosus. A Blalock-Taussig anastomosis was established. Subsequently, she was diagnosed with absent tricuspid valve, pulmonary atresia, and atrial septal defect. These were definitively treated surgically in 1990 when the patient was 5 years old via RV outflow tract plasty and atrial septal defect closure. Intraoperative findings included weak RV contraction and an anterior RV wall almost totally lacking myocardium. Five years after the operation, she suffered from ventricular tachycardia originating from the RV wall, which was treated by electrical cardioversion and subsequent administration of oral antiarrhythmic medication. Six months before admission, dyspnea …

Sildenafil ameliorates right ventricular early molecular derangement during left ventricular pressure overload

Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases.

Absence of Rapid Propagation through the Purkinje Network as a Potential Cause of Line Block in the Human Heart with Left Bundle Branch Block

Background: Cardiac resynchronization therapy is an effective device therapy for heart failure patients with conduction block. However, a problem with this invasive technique is the nearly 30% of non-responders. A number of studies have reported a functional line of block of cardiac excitation propagation in responders. However, this can only be detected using non-contact endocardial mapping. Further, although the line of block is considered a sign of responders to therapy, the mechanism remains unclear. Methods: Herein, we created two patient-specific heart models with conduction block and simulated the propagation of excitation based on a cellmodel of electrophysiology. In one model with a relatively narrow QRS width (176 ms), we modeled the Purkinje network using a thin endocardial layer with rapid conduction. To reproduce a wider QRS complex (200 ms) in the second model, we eliminated the Purkinje network, and we simulated the endocardial mapping by solving the inverse problem according to the actual mapping system. Results: We successfully observed the line of block using non-contact mapping in the model without the rapid propagation of excitation through the Purkinje network, although the excitation in the wall propagated smoothly. This model of slow conduction also reproduced the characteristic properties of the line of block, including dense isochronal lines and fractionated local electrocardiograms. Further, simulation of ventricular pacing from the lateral wall shifted the location of the line of block. By contrast, in the model with the Purkinje network, propagation of excitation in the endocardial map faithfully followed the actual propagation in the wall, without showing the line of block. Finally, switching the mode of propagation between the two models completely reversed these findings. Conclusions: Our simulation data suggest that the absence of rapid propagation of excitation through the Purkinje network is the major cause of the functional line of block recorded by non-contact endocardial mapping. The line of block can be used to identify responders as these patients loose rapid propagation through the Purkinje network.

Impact of age on left ventricular geometry and diastolic function in elderly patients with treated hypertension

Abstract Purpose: Left ventricular (LV) remodelling is observed in numerous patients with hypertension and is a principal cause of heart failure in elderly patients. The aim of this study was to determine the relationships between age and structural/functional LV remodelling observed in elderly hypertensive patients. Methods: A total of 557 elderly hypertensive patients (mean age: 74.0 ± 8.6 years) with preserved LV systolic function underwent echocardiography and 24-hour blood pressure (BP) measurement. Results: Overall, 41.1% of patients had LV hypertrophy, 77.9% had increased relative wall thickness (RWT) defined as RWT >0.42, and 31.8% had both. Logistic analysis of the entire study population showed that increased RWT was associated with both 24-hour systolic BP (odds ratio (OR) 1.38, 95% confidence interval (CI) 1.12 to 1.70) and age (OR 1.32, 95%CI 1.08 to 1.61), whereas increased RWT was associated only with age (OR 1.61, 95%CI 1.23 to 2.11) after excluding patients with LV hypertrophy. Univariate and multivariate linear regression analyses of all patients showed that LV diastolic echocardiographic parameters were consistently associated with age (p ≤ .001) alone, even considering LV structural changes. Conclusions: Age was independently correlated with LV concentric/functional changes regardless of LV hypertrophy, suggesting that ageing is independently involved in the progression of LV remodelling.